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November 1, 2013

AIDS Virus Protein Analysis Brings Researchers Closer To HIV Vaccine

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redOrbit Staff & Wire Reports - Your Universe Online

Scientists from The Scripps Research Institute (TSRI) and Weill Cornell Medical College have completed a new analysis of a key AIDS protein long considered to be one of the most difficult targets in structural biology, and their work is an important step forward in the development of an HIV vaccine.

In two separate papers published Thursday in Science Express, the online early edition of the journal Science, the researchers report that they have determined the first atomic-level structure of the tripartite HIV envelope protein.

Their findings provide the most detailed picture yet of the virus’s complex envelope, including sites that could be mimicked by future vaccines to produce an immune response. Currently, antiviral drugs are being used to treat the roughly 34 million HIV-infected people worldwide, but the medical community’s attempts to develop a vaccine to prevent infections and possibly even eradicate the illness have fallen short to date.

The biggest obstacle to a vaccine is Env, a name given to HIV’s envelope protein by virologists, the study authors explain. This protein’s structure is so delicate and complex that researchers have had trouble obtaining the protein in a form that is suitable to undergo atomic-resolution imaging.

“It tends to fall apart, for example, even when it’s on the surface of the virus, so to study it we have to engineer it to be more stable,” explained Andrew Ward, an assistant professor in TSRI’s Department of Integrative Structural and Computational Biology. Thus, the goal is to engineer a version of the Env trimer stable enough to be analyzed while maintaining nearly all of the original structural characteristics.

Ward, along with Ian A. Wilson, Bridget Carragher and other colleagues from TSRI, as well as John Moore, Rogier W. Sanders and other experts from Weill Cornell, successfully managed to produce a version of the protein that can survive atomic-level imaging work while including all of the trimer structure that normally sits outside of the viral membrane.

They then evaluated this new type of Env, dubbed BG505 SOSIP.664 gp140, using both X-ray crystallography and electron microscopy. The X-ray crystallography study marked the first time that the imaging technique had been used to analyze Env, while both methods resolved the trimer structure to a finer level of detail than has been reported before, the authors of the two research papers said.

“The new data are consistent with the findings on Env subunits over the last 15 years, but also have enabled us to explain many prior observations about HIV in structural terms for the first time,” explained Dr. Jean-Philippe Julien, a senior research associate in the Wilson’s laboratory and first author of the X-ray crystallography study.

“Arguably the most important implications of the new findings are for HIV vaccine design,” Weill Cornell reported in a statement. “In both of the new studies, Env trimers were imaged while bound to broadly neutralizing antibodies against HIV. Such antibodies, isolated from naturally infected patients, are the very rare ones that somehow bind to Env in a way that blocks the infectivity of a high proportion of HIV strains.”

Under ideal circumstances, an HIV vaccine would cause a tremendous release of these types of the vaccine would benefit from knowing the exact structural detail of the sites where the antibodies bind to the virus so that they can be mimicked. The authors said that the data they gathered is already being used towards vaccine development.

“We and others are already injecting the trimer into animals to elicit antibodies,” Dr. Ward said. “We can look at the antibodies that are generated and if necessary modify the Env trimer structure and try again. In this iterative way, we aim to refine and increase the antibody response in the animals and eventually, humans.”